Use of automated technology in chemical process research and development

ABSTRACT

A method and workstation for optimizing chemical processes based on combinatorial chemistry, automation technology, and computer-controlled design is disclosed. The workstation includes a synthesizer, an analyzer, a robot and computer in communication with the synthesizer and analyzer. The computer includes one or more programs for regulating reaction parameters such as temperature, pressure, concentration of reagents and employs statistical methods for optimizing multiple reaction parameters and for designing optimized experiments for further investigation.

RELATED APPLICATIONS

[0001] This application claims priority benefits under 35 U.S.C. § 119based on U.S. Provisional Patent Application Ser. No. 60/018,282 filedon May 24, 1996.

FIELD OF THE INVENTION

[0002] This invention relates to the use of automated technology inchemical process research and development. This technology includesautomated synthesis methodology, product structural characterization andpurity analysis, and computer-controlled design of experiments (DOE)planning and data interpretation. The invention represents a means bywhich chemical reaction identification and optimization can be greatlyaccelerated and more effectively conducted.

BACKGROUND OF THE INVENTION

[0003] Chemical process development is an optimization procedure bywhich conditions are discovered to produce a chemical productefficiently, cost-effectively, safely, and with high quality assurance.Fundamental to this process in the chemical industry is the chemicalreaction. The chemical reaction is affected by a wide range of physicalvariables. Since these variables are interdependent, the possiblecombinations and permutations of these variables are numerous. As aresult, an enormous effort must be undertaken to study the variouscombinations of variables in order to identify the optimal set ofconditions for conducting a given chemical reaction.

[0004] The current state of the art in chemical process developmentinvolves a manual survey of different reaction conditions, which is timeconsuming, labor intensive, and repetitive. For example, twelve solventsmight be suitable for a given reaction. However, for the individualchemist to set up, work up, and analyze data from more than fourexperiments at a time becomes a difficult task. As a result, the chemistis limited to running four reactions at a time.

[0005] In the interest of expediency, perhaps the chemist can spend oneday studying the choice of solvent for the reaction because many morevariables must be investigated. Although the data from twelve solventswould be very useful, the chemist only has time to investigate foursolvents. This process is then repeated for each of the other reactionvariables.

[0006] These variables might include concentration, reaction times,temperature, type of reagents, amounts of reagents, etc. Because thesevariables are dependent upon one another, the number of experiments tobe run quickly multiplies. The process becomes very repetitive. Thechemist becomes bored and the quality of work is likely to decline. Theend result is that only a small percentage of the possible combinationsof variables is investigated using the manual approach.

SUMMARY OF THE INVENTION

[0007] The use of automated technology in chemical process research anddevelopment is disclosed. This technology is applicable to automatedsynthesis methodology, product structural characterization and purityanalysis, and computer-controlled design of experiments (DOE) planningand data interpretation. The invention represents a means by whichchemical reaction identification and optimization can be greatlyaccelerated and more effectively conducted.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The following discussion will make reference to the accompanyingdrawing figures, wherein like reference numerals refer to like elementsin the various views, and wherein:

[0009]FIG. 1 is a diagram of the components of a preferred workstationfor implementing the invention;

[0010]FIG. 2 is a block diagram illustrating the flow of commands anddata between the computer and synthesizer, robotic arm and productanalyzer of FIG. 1;

[0011]FIG. 3 is flow chart illustrating the sequence of steps inperforming the preferred chemical reaction optimization routine usingthe equipment of FIG. 1;

[0012]FIG. 4 is an additional block diagram of the computer,synthesizer, robot, and analyzer; and

[0013]FIG. 5 is an additional flow chart of the sequence of steps inperforming the preferred chemical reaction optimization routine usingthe equipment of FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

[0014] A. System Overview

[0015] In this description, the novel application of automatedtechnology to chemical process development is disclosed. The basicconcept is to have a machine perform the repetitive procedures involvedin process development in order to increase the efficiency with whichdata can be collected and analyzed for a given chemical reaction.

[0016] A preferred workstation for implementing the invention is shownin FIG. 1. The workstation 10 includes a synthesizer 12 having areaction block 14 having, for example, 48 reaction wells 16. Thesynthesizer 12 preferably is equipped with a temperature control system18 for adjusting the temperature of the block 14, so as to control thetemperature of the wells 16. Preferably, the temperature control system18 has the capability of controlling the temperatures of the wellsindividually, so that the reaction conditions in the wells 16 can becustomized. The synthesizer includes a lid or cover 20. A source 22 ofnitrogen or argon gas is connected to the synthesizer 12 via a conduit24, which enables a control of the atmospheric conditions above thewells. Mixing mechanisms such as a vortex mixer or an orbital shaker canbe built into the synthesizer 12 to assist in the mixing of thechemicals in the wells.

[0017] The synthesizer 12 further includes a robotic arm assembly 26which has pipetting capability for selectively adding quantities of oneor more reagents to the wells 16. The robotic arm assembly 26 includesan X-Y drive mechanism 28 or other suitable means for controlling theposition of the pipetting tip portion 30 of the arm assembly relative tothe wells. The pipetting tip portion 30 further includes equipment forquenching the reactions in the wells 16 and for working up the desiredreactants. A synthesizer capable of operating experiments is by BohdamAutomation (Mundelein, Ill.) which features the automated synthesisworkstation capable of solid-phase and solution-phase synthesis,performing upwards of 48 simultaneous reactions. The reactions can runin an atmosphere and solvent of choice by the operator at temperaturesranging from −40° C. to +150° C.,

[0018] The station 10 also includes an analytical instrument 40 such asan HPLC or LC/MS for conducting analysis of the products of suchchemical reaction. The reaction products from the synthesizer 12 can beeither manually loaded into the analytical instrument 40, or loadedautomatically with the assistance of suitable robotic arms or otherequipment, represented by robot 50 in FIG. 2 or other suitablemechanical system.

[0019] The operation of the synthesizer 12 and analytical instrument 40is controlled by a computer 42, as shown in the block diagram of FIG. 2.The computer 42 regulates the environmental conditions in thesynthesizer 42 such as by controlling the temperature of the wells 16.The quantity and type of reagents added to the wells is also controlledby the computer 42, as is the position of the arm 26 relative to thewells 16. The computer 42 further initiates and controls the analysis ofthe chemical reaction products in the analytical instrument 40, andreceives the analytical data from the instrument 40. The computer 42further implements a design of experiment program (DOE) that is used toidentify the optimal conditions for the chemical reaction being studied,as described below. It will be understood that some or all of thecontrol functions of the computer 42 may be integrated into one or moreof the individual components of the system 10. Where the reactionproducts are automatically loaded into the product analyzer 40, thecomputer 42 controls a robot 50 to perform this task.

[0020] An additional block diagram of the computer, synthesizer, robot,and analyzer is shown in FIG. 4. The computer 42 contains a processor 64which communicates with non-volatile (read only memory, ROM 68) andvolatile (random access memory, RAM 70) memory devices. The processor 64also has a comparator 66 for comparing values. The processor 64 executesa computer program, as described subsequently in FIG. 5. The computerprogram is stored in the ROM 70 and executed either in the RAM 68 or theROM 70.

[0021] The processor 64 communicates with various subcomponents of thesynthesizer 12, the analyzer 40 and the robot 50. The synthesizercontains a temperature control system 18 which controls the temperatureof each of the individual wells of the block. The processor sends acommand to the temperature control system 18 specifying a certaintemperature for a particular well. The synthesizer also contains anagitator/mixer 76 which agitates or mixes the individual wells. Thereare two different methods of agitating or mixing. The first method is toagitate the block as a whole whereby each of the wells are shaken at thesame rate. To do this, the entire reaction block is agitated at onerate. The second method is to mix each of the individual wells atdifferent rates. Each well is equipped with at metal stirer underneaththe well. Inside the well is a TEFLON-coated magnet which follows themotion of the metal stirer underneath the well. In this manner, theindividual well is stirred based on the rate at which the metal stireris rotated. The rate of rotation is set by the processor 64.

[0022] The synthesizer also contains an atmospheric regulator 78 whichprotects the reactants in the wells if the reactants are sensitive tooxygen or water or other materials in the environment in proximity tothe well. Nitrogen or argon gas is dispensed from the source 22 throughthe conduit 24 based on a valve which is controlled by the valve motor80. The valve motor is controlled by the processor 64.

[0023] The synthesizer further contains a drive 28 for moving therobotic arm assembly 26. As described above, the robotic arm assembly 26has pipetting capability for selecting, obtaining and dispensing one ormore reagents. The pipetting capability is performed through a pipettingmechanism 74 which draws reagents through the pipetting tip portion 30and stores one or more reagents in the robotic arm assembly 26.Subsequently, the one or more reagents are dispensed via the pipettingmechanism 74 into the wells. Both the drive 28 and the pipettingmechanism 74 are controlled by the processor 64.

[0024] The analyzer 40 and robot 50 are in communication with theprocessor 64 as well. The processor 64 controls the drive 72 of therobot 50 which extracts samples from each of the wells. The samples aretransferred to the analyzer 40 which analyzes the contents of the samplesuch as the components of the reaction mixture including the product,the reactants, and any contaminants.

[0025] B. Methodology

[0026] Where the number of reagents is in the hundreds, hundreds ofthousands of different compounds are possible. The practical consequenceis that expanding the numbers of compounds under evaluation increasesthe probability of discovering a molecule with the desired biologicalproperties. Testing of combinations of compounds is done, with furthertesting performed based on interpretation of the results of the priortests. In this manner, optimization of the reaction is used insynthesizing the desired product through an iterative process of runningtests, interpreting the tests and generating new parameters of testingfor future tests based on the analysis of the current tests.

[0027] Automated process development is distinctly advantageous overmanual surveys of process conditions. The automated process is capableof executing significantly more tests at one time with less operatorinput. Further, the automated process development assists the operatorby analyzing the test results and suggesting parameters for furthertesting. Optimal conditions are defined by the operator for theparticular test. Ordinarily, conditions of interest to an operatorinclude: amount of yield; amount of by-products; amount of unreactedreagents; temperature and time of reaction.

[0028] A preferred automatic chemical process development techniqueaccording to the present invention is shown in flow-chart form in FIG.3, and will be described in conjunction with the system shown in FIG. 1.In Steps 1-3, the synthesizer 12 containing a 48-well reaction block 14is used for the reaction of interest, and the robotic arm 26 can beprogrammed to dispense precise amounts of reagents into each well (seeFIG. 1). Each well 16 contains a separate experiment. The temperaturewithin each well can be controlled and the contents of each well can beefficiently mixed. As an example of one possible study, with a 48-wellreaction block 14, twelve different solvent systems at four differentconcentrations can be investigated. The 48 reactions are then runsimultaneously in the time that only four reactions could be run in amanual approach. The reactions can then be quenched and worked up usingthe same robotic technology. This process alleviates the chemist fromperforming repetitive tasks and increases the efficiency with whichinformation can be gathered.

[0029] Once the 49 reactions are completed, at step 4 the tasks ofcompound analysis and data compilation begin. These processes can alsobe automated. The success of each of these 48 reactions can be evaluatedusing the analytical technique which was already developed for theparent reaction. For example, HPLC might be the analytical method ofchoice. In this case, the crude product mixtures would be manually orautomatically transferred to vials which fit in an HPLC autosampler 40.Analysis of each reaction mixture would be completed automatically andthe results would be compiled and analyzed by the computer 42. Thiscomputer 42 also controls the synthesizer 12 and the HPLC unit 40.

[0030] At this point (step 5), the chemist would determine how tointerpret the experimental data. If product yield is the primaryconcern, this can be calculated by quantitative analysis from HPLC data.Alternatively, the chemist may be interested in the reaction conditionswhich minimize a particular side product or may want to determine thechemical structure of a new side product. In the latter case, LC/MSwould be useful to gain additional information about the new sideproduct. LC/MS would be an alternative analytical method to BPLC.

[0031] The concept of statistical design of experiments (DOE) may beapplied to aid in experimental design (step 6). Commercially availablecomputer programs can, in fact, control the reaction conditions utilizedby the synthesizer to conduct the most effective DOE study. The computer42 can then correlate the data obtained on reaction yield, productpurity, etc. and extrapolate to propose, and subsequently confirm,optimal reaction conditions. This is represented by the arrow 50 in FIG.3. Basically, a new and more narrowly circumscribed set of reactionconditions are programmed in the synthesizer and robotic arm, and theprocess is repeated. This procedure could iterate several times, untilthe optimal reaction conditions are determined with the desired level ofprecision. Alternatively, the procedure (steps 1-5) could just beperformed once, with the computer 42 identifying which of the reactionwells 16 had the most favorable conditions for the reaction.

[0032]FIG. 5 is an additional flow chart of the sequence of steps inperforming the preferred chemical reaction optimization routine. Theprogram which executes the operation of the automated sequence ofoperations, as stated above, is resident either in RAM 68 or ROM 70. Theprogram first determines the initial values of reagent concentrationsand type of reagents for each of the wells 82. This is done so that theprocessor 64 can command the pipetting mechanism 74 to obtain thecorrect reagents and the approximate amount of reagents for use in allof the wells. As shown in FIG. 5, the total number of wells isdesignated as “X.” As discussed above, one reaction block 14 has, forexample, 48 reaction wells 16. Reaction blocks with less or morereaction wells may be used as well.

[0033] The processor 64 then instructs the drive 28 to a particular xand y position to obtain the reagents 84. The pipetting mechanism 74then stores the reagents in the dispenser of the drive of thesynthesizer 12. Then a loop is executed for each of the wells 16. Theprocessor 64 moves the motor of the drive 28 to the x and y position ofthe well 90, the reagent values and type of reagents is determined bythe processor 92, and the reagents are dispensed into the well. Thereagent values and type of reagents is determined by a parameter look-uptable 69 (which contains all of the relevant parameters for theexperiment) in the memory of the microprocessor. The reagent values andtype of reagents is either based on operator input or based on theoptimization scheme described subsequently.

[0034] Alternatively, the pipetting mechanism, rather than storing thereagents in the dispenser in one step and dispensing in another step mayalternatively store the reagents and dispense, sequentially for eachwell. Further, rather than automatic obtaining and dispensing of thereagents, the operator may manually input the reagent values into thewells.

[0035] Prior to execution of the program, a reagent-properties look-uptable is created which determines, for a specific reagent, whether thereagent is sensitive to oxygen or water. This reagent-properties look-uptable may be separate and distinct from the parameter look-up table 69,or may be combined for operator convenience. Based on thereagent-properties look-up table, if the reagent is sensitive to oxygenor water 100, the processor 64 opens the valve motor 80 to dispenseeither nitrogen or argon gas. Then, the clock for the processor 64 ischecked with the value stored as the start_time of the experiment 106. Aloop is then entered to set the temperatures of each of the wells. Thetemperature is determined for each well 108 by the parameter look-uptable 69. The temperature in the parameter look-up table 69 is eitherbased on operator input or based on the optimization scheme describedsubsequently. The processor 64 sends a command to the temperaturecontrol system 18 to set the temperature value 100.

[0036] The agitation/mixing of the synthesizer is next initialized basedon whether the individual wells are mixed at different rates or whetherthe entire reaction block is agitated at the same rate. If the agitationis at the same rate, the program determines the block agitation from theparameter look-up table 118 and sends a command to the agitator/mixer120. If the agitation is at different rates, the program enters a loopand determines the agitation from the parameter look-up table for eachwell 124 and sends a command to the agitator/mixer 126.

[0037] The reaction times are then determined for each of the wellsbased on data in the parameter look-up table 69. The wells are orderedbased on the reaction time, from lowest to highest 134; The reactiontimes are then checked based on checking the clock from the processor 64and subtracting the time from the start value 138. When the reactiontime has been exceeded for a particular well, the reaction is stopped142. Stopping the reaction can be done in several ways depending uponthe particular reaction. The heat may be removed, the agitation stopped,or some other material, such as water, an acid or a base, may be addedto stop the reaction. Then, based on the parameter look-up table 69, theprocessor determines whether to quench the entire reaction block 148.

[0038] After the reaction, the components of each of the wells 16 mustbe removed from each of the wells, sent to the analyzer 40 and analyzed.The processor 64 signals the drive 72 of the robot 50 to move to an xand y position 154, extract mixture from the well 156, and send themixture to the analyzer 158. The analyzer 40 then analyzes thecomponents of the reaction mixture and sends the results to theprocessor 64. The processor 64 examines the data from the analyzer 40and, based on a product table, determines the products of the yield ineach of the wells. This product table is input prior to operation of theprogram with each of the values which may be sent from the analyzerhaving a corresponding type of product based on that value. Someanalyzers perform this look-up table function itself and send the listof products back to the processor. The processor stores the analysis ina newly-created table and continues obtaining data for each of thewells.

[0039] The newly created table is then analyzed by the processor 64 inorder to determine the suggested parameters for the next experiment.

[0040] The initial reaction parameters such as temperature, time,concentration and/or pressure and the yield data obtained by theanalyzer for each of the initial experiments are then entered into theprogram. The program then processes the data, generates multivariablecontour maps or response surfaces which describe the behavior of thesystem of reaction parameters or variables, and designs a set of newexperiments based on the response surfaces. Methods for studyingrelationships among multiple parameters and for solving statisticalproblems related to these relationships are known and include the MonteCarlo method and rotating-simplex method of optimization, otherwiseknown as the self-directing optimization (SDO) method. A generaldiscussion of the useful statistical methods for solving statisticalproblems is included in C. Hendrix (1980) Chemtech, August 1980, pp.488-96 which is incorporated by reference in its entirety. It will beunderstood by the ordinary skilled artisan that the program may includeone or more suitable statistical methods for optimization of processeshaving multiple parameters and for designing experiments which includemultiple variables.

[0041] Using a program which utilizes the Monte Carlo method, forinstance, the operator can define the space of parameters to beanalyzed, run a series of random preliminary experiments in this space,define a new space of parameters using the best of these preliminaryexperiments, run additional experiments in the new space and continuethis process until no further improvement is observed. For example, theoperator defines a space of reaction parameters for each experiment suchas reaction temperature, concentration of reagent(s), pressure, and timeperiod then performs several preliminary random experiments using thesynthesizer. The analyzer data concerning reaction product yield, forinstance, are then stored in the computer as a parameter. Based on thepreliminary parameters and the product yield parameter, the program thenutilizes the statistical method to generate a new space of parameters(e.g., reaction temperature, concentration, pressure and time) forfurther experimentation. A new set of reactions are then performed withthe new space of parameters and the result product yield parameter isthen stored and processed by the Monte Carlo method as before. Thisprocess can be repeated until no further improvements in reactionproduct yield, for instance, are obtained.

[0042] Alternatively, a program which utilizes the SDO method generatesa set of experiments in all of the variables of interest for theoperator. When these experiment has been run, the experiment that gavethe worst result is identified among the set. This experiment is thendiscarded and replaced with a new experiment. When the replacementexperiment has been run, the worst of the set is again identified anddiscarded. This process continues until no further improvement isobserved. For example, the operator performs preliminary experimentswith the synthesizer using SDO variables of interest. The reaction yielddata, in combination with the variables, are then analyzed by theprogram. The program would then eliminate the experiment with the worstresult, e.g., worst yield, and generate a new proposed experiment. Thisprocess is repeated until no further improvements in product yield, forinstance, are obtained.

[0043] Another method to analyze the data in the newly created table isby first determining the “weights” for each of the reaction parameters172. The reaction parameters include the total product yield, the amountof contaminants, the amount of unreacted reagents, the time of thereaction, the temperature of the reaction and the agitation/mixing ofthe reaction. Prior to execution of the program, the operator assigns“weights” based on importance of each reaction parameter. In thismanner, the results of each of the wells can be assigned a total “score”by multiplying the reaction parameters by the “weights” and adding them.For example, if the total product yield and the total time are the twoparameters of interest, and the total product yield is considered moreimportant than the time of the reaction, the “weights” for each can be0.8 and 0.2, respectively for each of the two parameters. Each of theresults for an individual well can then be tallied 174. For parameterswhich are more desirable when they are lower in value, e.g. the time ofreaction, the result of multiplying the weight by the parameter can beinverted, and then added to the total to determine the “score.”

[0044] The entries can then be arranged based on the score 180. Theprocessor 64 then displays the results of the raw data and the “scores”182. At each step in the methodology, the display can be updated toinform the operator of the current reaction. For example, when theprocessor 64 commands or receives information from the synthesizer 12,the analyzer 40 or the robot 50, the display can be updated to indicatethe current operation.

[0045] Based on the highest ranked “score,” the suggested bounds for thenext set of experiments are determined 184, 186. For example, if thetemperature of the reaction is determined to be an important parameter,the temperature value of the highest ranked “score” is used as a basevalue for the temperature bounds for the next set of experiments. Thesuggested parameters is then displayed to the operator 188.

[0046] This automated process development technology allows a vast arrayof data to be collected and interpreted. Many combinations of reactionvariables can be investigated in a short time period. Using the currentmanual technology, only a local optimization is found because it is tootime consuming to investigate every set of reaction conditions. With thenew automated technology presented here, a large number of statisticaldata points can be collected. In essence, a global optimization isfound. The amount of data generated by this process is limited only bythe number of variables that can be envisioned for a given reaction.

[0047] Some components of the automated technology discussed in thisdisclosure have found application in combinatorial chemistry for thearea of drug discovery. As a result, robotic technology and automatedsynthesizers, as well as HPLC and LC/MS instruments are commerciallyavailable. The novel integration and application of these methods tochemical process research and development, however, has not been pursuedto the best of our knowledge.

[0048] The hardware elements of the workstation of FIG. 1 are generallyknown in the art and either commercially available or described in theliterature. See, for example, U.S. Pat. Nos. 5,443,791 and 5,463,564which are incorporated by reference herein. A suitable synthesizer isavailable from Advanced ChemTech of Louisville, Ky., model no. 4906 MOSand from Bohdan Automation, Inc. of Mundelein, Ill., RAM® synthesizer.Robotic arm 26 mechanisms are incorporated into the automatedsynthesizer equipment of Advanced Chemtech and Bohdan Automation.Suitable HPLC and LC/MS analytical instruments equipped withautosamplers are widely available. The synthesizer, robotic arm, andanalytical instruments typically come with their own resident computersoftware, which can be readily modified or augmented by persons of skillin the art to accomplish the chemical process and design ofexperimentation methodology described herein. A suitable analyticalinstrument capable of ascertaining purity and structure is the FinniganMAT (San Jose, Calif.) liquid chromatograph/mass spectrometer(LC/MS/MS).

What is claimed is:
 1. A method for chemical synthesis using asynthesizer, an analyzer, and a computer, the method including the stepsof: dispensing the reagents into a plurality of wells in a reactionblock; reacting in the synthesizer the reagents using various operatingconditions; obtaining a sample from the plurality of wells; analyzingthe sample using the analyzer to determine the components of the sample;analyzing the components of the sample and the various operatingconditions to generate a statistical analysis; and generating suggestedparameters for future experiments based on the statistical analysis. 2.The method as claimed in claim 1 wherein the step of reacting in thesynthesizer the reagents using various operating conditions includesmodifying the temperature of the well.
 3. The method as claimed in claim2 wherein the step of reacting in the synthesizer the reagents usingvarious operating conditions includes reacting the reagents by mixingthe reactants in the well.
 4. The method as claimed in claim 1 furthercomprising the step of stopping the reaction in the wells prior toobtaining a sample from the plurality of wells.
 5. Apparatus forchemical synthesis comprising; a computer; a synthesizer incommunication with the computer, the synthesizer having a reaction blockcontaining a plurality of wells, the synthesizer also having devices tocontrol the atmospheric conditions of the reactions in the plurality ofwells; an analyzer in communication with the computer, the analyzeranalyzing the components of the reactions; the computer having aprocessor for sending commands to the synthesizer to control theatmospheric conditions, the processor also having a parameter look-uptable containing the parameters for the reaction, the processor furtherreceiving the analysis from the analyzer of the components of thereactions and generating a statistical analysis based on the componentsof the reactions and the parameters of the reaction, the processorgenerating suggested parameters for future experiments based on thestatistical analysis.